期刊
CIRCULATION RESEARCH
卷 104, 期 11, 页码 1283-U112出版社
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/CIRCRESAHA.109.194423
关键词
genetics; gene expression; sodium channels; conduction; mouse mutants
资金
- Netherlands Heart Foundation [2003/B195, 2005/T024]
- Interuniversity Cardiology Institute of the Netherlands [06401]
- Fondation Leducq Trans-Atlantic Network of Excellence [05CVD01]
- Netherlands Organization for Scientific Research [ZonMW Vici 918.86.616]
Conduction slowing of the electric impulse that drives the heartbeat may evoke lethal cardiac arrhythmias. Mutations in SCN5A, which encodes the pore-forming cardiac sodium channel alpha subunit, are associated with familial arrhythmia syndromes based on conduction slowing. However, disease severity among mutation carriers is highly variable. We hypothesized that genetic modifiers underlie the variability in conduction slowing and disease severity. With the aim of identifying such modifiers, we studied the Scn5a(1798insD/+) mutation in 2 distinct mouse strains, FVB/N and 129P2. In 129P2 mice, the mutation resulted in more severe conduction slowing particularly in the right ventricle (RV) compared to FVB/N. Pan-genomic mRNA expression profiling in the 2 mouse strains uncovered a drastic reduction in mRNA encoding the sodium channel auxiliary subunit beta 4 (Scn4b) in 129P2 mice compared to FVB/N. This corresponded to low to undetectable beta 4 protein levels in 129P2 ventricular tissue, whereas abundant beta 4 protein was detected in FVB/N. Sodium current measurements in isolated myocytes from the 2 mouse strains indicated that sodium channel activation in myocytes from 129P2 mice occurred at more positive potentials compared to FVB/N. Using computer simulations, this difference in activation kinetics was predicted to explain the observed differences in conduction disease severity between the 2 strains. In conclusion, genetically determined differences in sodium current characteristics on the myocyte level modulate disease severity in cardiac sodium channelopathies. In particular, the sodium channel subunit beta 4 (SCN4B) may constitute a potential genetic modifier of conduction and cardiac sodium channel disease. (Circ Res. 2009; 104: 1283-1292.)
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据